Re spiro-(steroid-17,2&#39;-furan-3&#39;-ones) and a process for their manufactu

ABSTRACT

COMPOUND OF THE FORMULA   (2-(R&#39;&#39;-CH(-ST)-),3-(O=),5-R-2,3-DIHYDROFUR-2-YL)-   WHEREIN   R=HYDROGEN, LOWER ALKYL, ARYL OR ARALKYL R&#39;&#39;=HYDROGEN, METHYL, FREE OR ESTERIFIED HYDROXYL OR BHALOGEN ST=THE RESIDUE OF A SUBSTITUTED OR UNSUBSTITUTED, SATURATED OR UNSATURATED STEROID RING. FOR EXMAPLE: 9A-FLUORO-11B-HYDROXY-5&#39;&#39;,16A-DIMETHYLSPIRO-(ANDROST-1,4-DIENE-17A,2&#39;&#39;-FURANE -3,3-DIONE). USE: ANTI-INFLAMMATORY OR GESTAGENIC AGENTS.

United States Patent "ice ew, 531727312 3 Compounds to be particularly highlighted are those 3,757,009 of formula SPIBO-[STEROID-17,2-FURAN-3'-ONES] AND A PROCESS FOR THEIR MANUFACTURE O=C--(|;/H Georg Anner, Basel, Switzerland, assignor to Ciba-Geigy R C-R Corporation, Ardsley, N.Y. 5

No Drawing. Filed Mar. 2, 1971, Ser. No. 120,363 Claims priority, application Switzerland, Mar. 6, 1970, 3,287/70 Int. Cl. C07c 173/00 US. Cl. 260--239.55 R 3 Claims 10 0 1'1. wherein R in particular represents hydrogen or a lower alkyl radical, such as methyl, ethyl or propyl, R represents hydrogen or a methyl or hydroxyl group, R denotes a ABSTRACT OF THE DISCLOSURE Compounds of the formula g free or esterified hydroxyl group in the 5-position, to- 7 R gether with a hydrogen atom, or an oxo group, and R 0 and R denote hydrogen or a halogen atom, especially St fluorine, and which can also possess further double bonds A in the 1- and/or 6-position. These compounds are particularly active as anti-inflammation agents, as can be demwherein onstrated in the foreign body granuloma test on rats, Rzhydrogfin, lower alkyl, aryl or aralkyl glgulythe compound are administered systemically or ij gg g methyl free or estenfied hydroxyl or ,3- Further compounds to be highlighted are those of St=the residue of a substituted or unsubstituted, saturated formula or unsaturated steroid ring. -E For example: 9a-flnoro-11B-hydroxy 5',16a dimethylspiro- [androst-1,4-diene-l7a,2'-furane-3 ,3-dione] Use: anti-inflammatory or gestagenic agents. --R

The subjects of the present invention are new spiroi [steroid-17,2'-furan-4'-0nes] of partial formula O=00H and their 3-ketals and 3-enol-ethers, wherein R has the significance given above and R represents a methyl group 17 a or a hydrogen atom and R in particular represents hydrost 16 O I 40 gen or a lower alkyl radical, such as methyl, ethyl or v propyl. H 7 I A further important group of new compounds corre:

sponds to the formula wherein R represents hydrogen, a saturated hydrocarbon 0:0 CH

radical, such as as an alkyl radical, preferably a lower g alkyl radical, such as the methyl radical, or an aryl or R aralkyl radical, such as an unsubstituted or substituted 0 phenyl or phenyl-lower alkyl radical, it being possible for the aromatic nuclei to be substituted, for example by halogen atoms, trifiuoromethyl groups, free esterified or etherified hydroxyl groups and/or lower alkyl groups, R 5

represents hydrogen, a methyl group in the a: or fi-posi tioll 9 a free or esterified hydfoxyl grouainthe 1 1 wherein R has the significance given above, R in parv as met y et y or propy an 5 enotes a ree, es errof a substituted or unsubstituted, saturated or unsaturated, fi d or th ifi d d l group, S erol. i' An esterified hydroxyl group is, in'particular, a hy- Thls fad1ca1 9f a ring can for example h droxyl group which is esterified with a lower aliphatic double bonds II! 19 9 4 6 anfl/or O carboaylic acid, such as acetic, propionic, butyric or 53 all g i 5515 and mlaftlculal' l g i caprolc acid, an aromatic carboxylic acid, such as benaolc 1 uents,f suc 22s fgwg a g'h gtgl fi g 1 l? 6 Y. acid, or their derivatives which are SllbStltH-Cijl in the ring, p fee, 68 6Y1 6 0f 6 6T1 6 Y Y P fee for example by me oxy groups and/or ao en atoms ktftalised 0X0 gIOUPSaPd/OY halogen P Such as for example p-bromobenzoic acid or 3,4,5-tiimethoxy fluorine, bromine or Chlorlne atoms, 1n POSIUOIIS 3, 9 benzoic acid, or with an araliphatic carboxylic acid, such and/or 11. as an appropriate phenylacetic acid.

The compounds mentioned represent a new Class Of An etherified hydroxyl group is, in particular, a lower steroids and possess valuable pharmacological properties. lk l group, h as th methoxy 01' ethoxy grou a Thus they possess, in particular, an anti-inflammation, cycloalkyloxy group, such as the cyclopentyloxy group, gestagenic, anti-androgenic, oestrogenic and/or blood an aryloxy group, such as the phenyloxy group, or their cholesterol-lowering activity. .They can also serve as inter- 70 derivatives which are substitutedby methoxy groups and/ mediate products for the manufacture of other pharmaco or halogen atoms in the ring, .such as p-bromophenyloxy logically active compounds. v Y or p-chlorophenyloxy groups or an aralkyloxy group, such wherein R, R' and St have the abovementioned significance or a compound of the partial Formula II CHz-C -R wherein R and St have the abovementioned significance, is treated with a strong acid, in particular a strong inorganic acid such as a hydrogenhalide, sulfuric acid or perchloric acid, and, if desired, a 3-oxo group is converted into a ketalised or enolised oxo group or a ketalised or enolised 3-oxo group is liberated.

The elimination of water can be effected by heating, for example to ISO-250 C., especially by sublimation, primarily in a high vacuum or by heating in a high-boiling inert solvent, such as diphenylmethane. The elimination of water can however also be eifected by treatment with an acid, for example a strong mineral acid, such as hydrochloric acid, or a sulphonic acid, such as methanesulphonic acid or p-toluenesulphonic acid, or also with Lewis acids, for example ferric chloride. This reaction is preferably carried out in a solvent, such as a lower alcohol, for example methanol or ethanol, a lower halogenated hydrocarbon, such as methylene chloride or their mixtures.

'A 3-oxo group can be converted into a ketalised or enolised oxo group, or a ketalised or enolised oxo group converted into the free 3-oxo group, simultaneously with the elimination of water or also in a separate step. This reaction takes place in a manner which is in itself known.

The treatment of the compounds of the partial Formula II with a strong acid can be effected in an appropriate solvent, such as a lower aliphatic organic acid, e.g. acetic or propionic acid, a lower aliphatic alcohol, e.g. meth anol, ethanol, propanol or tert. butanol. Preferably the strong acid, such as the halogen halides, e.g. hydrochloric, hydrobromic or hydriodic acid are used solved in acetic acid or the hydrofluoric acid in the presence of urea or dimethylformamide.

The starting substances used according to the invention can be obtained in accordance with our U.S. Pat.

application Ser. No. 72,842 of Sept. 16, 1970, from the appropriate 21-S-CO-R compounds [21-acyl sulphides] by treatment with bases which are sufficiently strong to deprotonise the methylene group carrying the S, and optionally in the presence of a thiophilic compound. As bases, lower trialkylamines are especially used for this purpose, such as triethylamine, in the presence of lithium salts of strong inorganic acids, for example lithium perchlorate, and as a thiophilic compound organic derivatives of 3-valent phosphorus, such as triphenyl-phosphine, are especially used.

The starting substances of the partial Formula II may also be prepared by treating a corresponding compound non-substituted in 21-position according to Claisen, for example with an ester of an aliphatic carboxylic acid, such as acetic acid ethyl ester of formic acid ethyl ester in the presence of a strong base such as sodium hydride, amide or alcoholate.

The invention also relates to those embodiments of the process'in which a starting substance is formed under the reaction conditions or is used in the form of one of its derivatives.

The new compounds can for example be used in the form of pharmaceutical preparations in which they are contained in the free form or, where appropriate, in the form of their salts, mixed with a pharmaceutical, organic or inorganic, solid or liquid excipient suitable for enteral, parenteral or topical administration. Possible substances, for forming the excipient are those which do not react with the new compounds, such as water, gelatine, lactose, starch, stearyl alcohol, magnesium stearate, talc, vegetable oils, benzyl alcohols, gum, propylene glycols, white petroleum jelly, cholesterol or other known medicinal excipients. The pharmaceutical preparations can for example be in the form of tablets, drages, capsules, ointments or creams or in a liquid form as solutions, suspensions or emulsions. They are optionally sterilised and/or contain auxiliary substances, such as preservatives, stabilizers, wetting agents or emulsifiers, solubilising agents or salts for regulating the osmotic pressure or buffers. They can also contain other therapeutically valuable substances. The pharmaceutical preparations are formulated according to the usual methods.

The new compounds can also be used in veterinary medicine, for example in one of the abovementioned forms, or in the form of feedstuifs or additives to animal fodder. Herein the usual extenders and diluents or feedstutfs are for example used.

The examples which follow explain the invention without however restricting it in any way.

EXAMPLE 1 1 g. of 9a-fiuoro-16a-mthyl-11p,17a-dihydroxy-21- acetyl-pregna-1,4-diene-3,20-dione is heated to about 200 C. in a high vacuum, in the course of which 9a-fluoro- 11p hydroxy 5',-16oz dimethyl spiro-[androsta-1,4- diene-17u,2-furane-3,3-dione] sublimes. After crystallisation from methylene chloride-ether the melting point is 290-293 C. (with decomposition). The ferric chloride reaction is negative.

The same end product is obtained if 0.1 g. of the starting substance mentioned is dissolved in 3 ml. of methanol, 0.5 ml. of 5% strength aqueous ferric chloride solution is added, and the solvent is largely allowed to evaporate overnight at room temperature, whilst stirring. After addition of water the product is filtered oflF, washed with water and taken up in methylene chloride, and after washing with water and drying the solvent is evaporated in vacuo.

A strong acid can be used instead of the ferric chloride for the ring closure. If, for example, 0.1 g. of the starting substance mentioned are dissolved in 3 ml. of methanol, mixed with 0.5 ml. of 2 N hydrochloric acid and stirred overnight in accordance with the above data and worked-up, the desired end substance is again obtained.

If, in the above example, 6a,9a-difluoro-l6u-methyl- 115,170; dihydroxy 21 acetyl-pregna 1,4-diene-3,20- dione is used as the starting substance, 6u,9oi-difiuoro-5', 16a dimethyl spiro [androsta 1,4 diene 17a,2' furane 3,3'-dione] is obtained, which melts at 310 C., with decomposition, after crystallisation from methanol or methylene chloride-ether.

EXAMPLE 2 0n sublimation in a high vacuum at about C., hydroxy 21 acetyl pregn 4 ene 3,20-dione yields spiro-[androst 4 ene-l7a,2'-furane-3,3-dione], which melts at 171-173" C. after recrystallisation from methylene chloride-ether.

The'cyclising elimination of water can also be effected by means of ferric chloride or a mineral acid, in accordance with the data in Example 1.

EXAMPLE 3 2l-acetyl-pregna-l,4-diene-3,l1,20-

trion iurane-3,311-trione1.

EXAMPLE 4 l g. of 17a hydroxy-Zl-acetyl-pregn-4-ene-3,20-dione is suspended in 100 ml. of benzeen and 6 ml. of ethylene glycol. After adding 25 mg. of p-toluenesulphonic acid monohydrate the mixture is boiled under reflux whilst stirring and the water formed is separated oif using a water separator. After 4 hours the mixture is cooled to C., 20 ml. of saturated sodium bicarbonate solution are added, the whole is well mixed, and the benzene solution separated OE and twice washed with water. Thereafter the solvent is dried and evaporated in vacuo. The crystalline residue is mixed with 0.1 ml. of pyridine and recrystallised from methylene chloride-ether. 3,3-Ethylenedioxy spiro [androst 5 ene-l7u,2-furan-3-one] is obtained. Melting point=222-231 C.

On splitting the 3-ketal with p-toluenesulphonic acid monohydrate in acetone, the spiro-[androst-4-ene-17a,2'- furane-3,3'-dione] described in Example 2 is obtained.

9a fluoro 16a methyl-11 3,17a-dihydroxy-21-acetylpregn-4-ene-3,20-dione can be converted analogously into 3,3 ethylenedioxy 9oz fluoro 11fi-hydroxy-5,16adimethylspiro- [androst-S -ene- 17 a,2'-furan-3 '-one] The starting substances used in the preceding examples can for example be obtained in the following manner:

EXAMPLE 5 100 ml. of benzene are poured over a mixture of 4.5 g. of 9a fluoro 16ct-meth'yl-l1fi,17a-dihydroxy-2l-mercapto-pregna-1,4-diene-3,20-dione-2l-S-acetate, 6.55 g. of triphenylphosphine, 2.76 g. of lithium perchlorate (anhydrous) and 10.7 ml. of triethylamine. A stream of nitrogen is passed over the suspension. After 71 hours stirring at 24 C. the solvent which has partly been entrained by the nitrogen is replaced, the mixture is stirred for a further /2 hour and filtered, and the filter residue is washed with 100 ml. of benzene. Evaporation of the benzene solution yields a mixture of triphenylphosphine and triphenylphospine-sulphide, which is discarded. The filter residue is introduced into a separating funnel together with 50 ml. of 2 N hydrochloric acid and 150 ml. of ice/water and extracted with methylene chloride. The methylene chloride extract is again Washed with hydrochloric acid and subsequently with water. After evaporation of the methylene chloride solution in vacuo at about 35 C., a crystalline residue is obtained which according to examination by thin layer chromatography does not contain any starting material. Ferric cloride reaction: red-brown. The residue is now stirred with 30 ml. of methylene chloride and filtered oif. The colourless crystal powder is easily soluble in methanol. For recrystallisation, it is dissolved in a little methanol, a large amount of methylene chloride is added and the mixture concentrated by evaporation, with displacement of the methanol until crystallisation occurs. The 9a-fluoro-16a-methyl-1 113,170:- dihydroxy 21 acetyl pregna-1,4-diene-3,20-dione thus obtained contains 1 mol of methylene chloride of crystallisation, and melts at 159-161 C., with evolution of methylene chloride.

The desulphurisation can also be effected in dimethylforrnamide, for example at 70 C.

6a,9a-difiuoro-lGa-methyl-I1fi,17a dihydroxy-Zl-mercapto-pregna-1,4-diene-3,20-dione-2l-S-acetate can be converted into 6a,9u-difluoro-16a-methyl-l1;8,17a-dihydroxy- 2l-acetyl-pregna-1,4-diene-3,20-dione (ferric chloride reaction: wine-red) analogously to the above data.

Starting from the following 21-acyl sulphides, the starting substances used above can be obtained analogously:

21-aeyl sulphides Starting substances 17a-hydr0xy-21-mereapto-pregn-4- 17m-hydroxy-21-acetyl-pregn-4- one-3,20-dione-21-Sacetate. ene-3,20-dione.

3-methoxy-l7a-hydroxy-21-mereapto- 3-methoxy-l7a-hydroxy-2l-acetylpregna 1,3,5-(10)trien-20one-21- pregna-1,3,5(10)-trien-Z0-one.

S-aeetate. 17a-hydroxy-2l-rnercapto-lQ-nor- 17a-hydroxy-2l-acetyl-lQ-norpteg11+ene-3,20-dione.

EXAMPLE 6 4 g. of 35-hydroxy-16a,17a-oxido-21-formyl-A -pregnen-20-on are mixed while stirring with 40 ml. of acetic acid, cooled to 12 to 13 C. and dropwise a solution of hydrobromic acid in acetic acid (1 part of volume hydrobromic acid of 30%, 2 parts of volume glacial acetic acid) added. After one hour the reaction mixture is poured over a solution of 40 g. of sodium acetate in 400 ml. of water and the crystalline precipitate filtered ofl After washing with water, the residue is dissolved in methylenechloride, the solution washed twice with water, then dried and evaporated in vacuo. The spiro-[3/3-hydroxy-16B- bromo-androst-4-en-17a,2'-furan-3-on] thus obtained is recrystallized from methylene chloride. Melting point 157-158 (decomp.).

1.8 g. of the crude spiro-[3,8-hydroxy-16p-bromoandrost-4-en-16a,2-furan-3-on] are dissolved in 35 ml. of pyridine and 17.5 ml. of acetic acid anhydride and stirred under nitrogen at room temperature for 12 hours. The brownish colored reaction mixture is dropped while stiring into a mixture of ml. of water and 30 g. of ice. The crystalline precipitate is filtered ofif, washed with water and then dissolved in methylene chloride. The solution obtained is washed with 2-n hydrochloric acid and water, dried and evaporated under vacuum. The thus obtained spiro-[3fl-acetoxy-16/3 brom-androst-S-en-17u,2- furan-3-on] melts after crystallization from methylenechloride-acetone at 263267 C.

Starting from the corresponding 21-formyl-compounds, the following compounds are obtained analogously:

19-nor-pregna-1,3,5(10)trien-20 The compounds used as starting material in this example may be obtained as follows:

To a mixture of 32 ml. of formic acid ethyl ester and 170 ml. of benzene there is added while cooling with ice and stirring under nitrogen, 12.8 g. of sodium methylate. After half an hour 13.2 g. of 3B-hydroxy-16a,17ot-oxido- A -pregnan-20-on are added. The reaction mixture is stirred 16 hours at 0-5 C. and then poured on a mixture of ml. of water, 100 g. of ice and 14 ml. of glacial acetic acid. The benzene layer is separated, washed neutral with water, dried and evaporated under vacuo. The residue obtained as brownish colored foam is the 3fi-hydroxy-16a,17a oxido-21-formyl-A -pregnen-20 on,

as] R wherein R is (1) a free or esterified hydroxyl group in the {3-position together with a hydrogen atom or (2) an oxo group, R and R are each hydrogen or halogen, at least one of R and R being halogen, R is hydrogen or methyl, R is hydrogen, lower alkyl, phenyl, phenyl-lower alkyl or phenyl-lower akyl substituted on the phenyl ring by halogen, trifiuoromethyl, hydroxyl, esterified hydroxyl, etherified hydroxyl or lower alkyl, and R is hydrogen, methyl, hydroxyl, esterified hydroxyl or halogen in the B-position, each of said esterified hydroxyl groups being derived from a lower aliphatic carboxylic acid, benzoic acid, benzoic acid ring-substituted by methoxy or halogen or phenyl-acetic acid, and each of said etherified hydroxyl groups being derived from a lower alkanol, a cycloalkanol, phenol, methoxy-substituted phenol and halosu'bstituted phenol.

2. A compound as claimed in claim 1, wherein R stands for methyl, R is hydrogen, R represents a fl-positioned hydroxy group together with a hydrogen atom or an oXo group, R stands for hydrogen or a fluorine atom and R represents a fluorine atom.

3. Compounds as claimed in claim 1, having the formula wherein R represents hydrogen or a fluorine atom and R stands for a fluorine atom.

References Cited UNITED STATES PATENTS 3,158,620 11/1964 Brown et al. 260239.55 3,205,243 9/1965 Riano et al. 260-397.4 3,424,750 1/1969 Fried 260239.55 3,420,820 1/1969 Stache et al. 260-239.57 3,547,912 12/1970 Lefebvre 260239.55

HENRY A. FRENCH, Primary Examiner US. Cl. X.R. 260999 

